CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of thalidomide is not fully understood. Thalidomide possesses immunomodulatory, antiinflammatory and antiangiogenic properties. Available data from in vitro studies and clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration.3-6 For example, administration of thalidomide has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL)3, however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients.7 Other antiinflammatory and immunomodulatory properties of thalidomide may include suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells. Thalidomide treatment of multiple myeloma patients is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma (T cell-derived cytokines associated with cytotoxic activity). Thalidomide was found to inhibit angiogenesis in a human umbilical artery explant model in vitro. The cellular processes of angiogenesis inhibited by thalidomide may include the proliferation of endothelial cells.
Pharmacokinetics and Drug Metabolism
Absorption
The absolute bioavailability of thalidomide from THALOMID® (thalidomide) Capsules has not yet been characterized in human subjects due to its poor aqueous solubility. However, the capsules are 90% bioavailable relative to an oral PEG solution. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) of THALOMID® (thalidomide) ranged from 2.9 to 5.7 hours indicating that THALOMID® (thalidomide) is slowly absorbed from the gastrointestinal tract. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (Cmax) increased in a less than proportional manner (see Table 1 below). This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.
Table 1: Pharmacokinetic Parameter Values for THALOMID® (thalidomide) Mean (%CV) Population/
Single Dose |
AUC0∞
µg · hr/mL
|
Cmax
µg/mL
|
Tmax
(hrs)
|
Half‑life
(hrs)
|
| Healthy Subjects (n=14) | | | | |
| 50 mg | 4.9 (16%) | 0.62 (52%) | 2.9 (66%) | 5.52 (37%) |
| 200 mg | 18.9 (17%) | 1.76 (30%) | 3.5 (57%) | 5.53 (25%) |
| 400 mg | 36.4 (26%) | 2.82 (28%) | 4.3 (37%) | 7.29 (36%) |
| Patients with Hansen’s Disease (n=6) | | | | |
| 400 mg | 46.4 (44.1%) | 3.44 (52.6%) | 5.7 (27%) | 6.86 (17%) |
Coadministration of THALOMID® (thalidomide) with a high fat meal causes minor (<10%) changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to approximately 6 hours.
Distribution
In human blood plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide.8 In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen.
Metabolism
At the present time, the exact metabolic route and fate of thalidomide is not known in humans. Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple products. In a repeat dose study in which THALOMID® (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism.
Elimination
As indicated in Table 1 (above) the mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing. As noted in the metabolism subsection, the precise metabolic fate and route of elimination of thalidomide in humans is not known at this time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than 0.7% of the dose excreted in the urine as unchanged drug. Following a single dose, urinary levels of thalidomide were undetectable 48 hrs after dosing. Although thalidomide is thought to be hydrolyzed to a number of metabolites,9 only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide was identified in the urine of subjects 12 to 24 hours after dosing.
Pharmacokinetic Data in Special Populations
HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single dose administration of THALOMID® (thalidomide) Capsules.
Patients with Hansen’s Disease: Analysis of data from a small study in Hansen’s patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID® (thalidomide). The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown.
Patients with Renal Insufficiency: The pharmacokinetics of thalidomide in patients with renal impairment have not been determined. In a study of 6 patients with end-stage renal disease, thalidomide (200 mg/day) was administered on a non-dialysis day and on a dialysis day. Comparison of concentration-time profiles on a non-dialysis day and during dialysis where blood samples were collected at least 10 hours following the dose, showed that the mean total clearance increased by a factor of 2.5 during hemodialysis. Because the dialysis was performed 10 hours following administration of the dose, the drug-concentration time curves were not statistically significantly different for days patients were on and off of dialysis. Thus, no dosage adjustment is needed for renally-impaired patients on dialysis.
Patients with Hepatic Disease: The pharmacokinetics of thalidomide in patients with hepatic impairment have not been determined.
Age: Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen’s disease ranging in age from 20 to 69 years does not reveal any age-related changes.
Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years.
Gender: While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values.
Race: Pharmacokinetic differences due to race have not been studied.
Clinical Studies
Clinical Study in Multiple Myeloma:
The efficacy of THALOMID® (thalidomide) in multiple myeloma was demonstrated in a randomized, multi-center open-label study of 207 newly diagnosed patients. This study randomized symptomatic patients with newly diagnosed multiple myeloma to THALOMID® (thalidomide) plus dexamethasone (Thal + Dex; N = 103) versus dexamethasone alone (Dex alone; N=104). The THALOMID® (thalidomide) dose was 200 mg daily and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and 17-20 every 28-days. Each group was treated for four 28-day cycles.
Baseline demographic and disease characteristics for the study population are summarized in Tables 2 and 3 respectively.
Table 2: Baseline Patient Demographics
Characteristic | Thal + Dex
(N=103)
| Dex alone
(N=104) |
|---|
|
1Missing information for 1 patient in the Dex alone group
2Missing information for 1 patient per arm
|
| Age (years) | | |
| Median | 65 | 68 |
| Range | 37 – 83 | 38 – 83 |
| Gender1 | | |
| Male | 53 (51%) | 61 (59%) |
| Female | 50 (49%) | 42 (40%) |
| Race2 | | |
| Caucasian | 90 (87%) | 90 (87%) |
| Black | 11 (11%) | 11 (11%) |
| Other | 1 (1%) | 2 (2%) |
Table 3: Baseline Disease Characteristics
Characteristic | Thal + Dex
(N=103) | Dex alone
(N=104) |
|---|
|
1Missing information for 1 patient in Thal + Dex arm
2Missing information for 19 patients in Thal + Dex arm and 20 patients in Dex alone arm
3Missing information for 17 patients in Thal + Dex arm and 30 patients in Dex alone arm
4Missing information for 16 patients in Thal + Dex arm and 11 patients in Dex alone arm
|
| Stage (Durie-Salmon), N (%) 1 | | |
| I | 14 (13.6%) | 17 (16.3%) |
| II | 47 (45.6%) | 44 (42.3%) |
| III | 41 (39.8%) | 43 (41.3%) |
| Immunoglobulin Type, N (%) 2 | | |
| IgA | 21 (20.4%) | 22 (21.2%) |
| IgG | 63 (61.2%) | 60 (57.7%) |
| IgM | 0 (0.0%) | 1 (1.0%) |
| Biclonal | 0 (0.0%) | 1 (1.0%) |
| Lytic Lesions3 | | |
| None | 28 (27.1%) | 14 (13.5%) |
| 1-3 lesions | 24 (23.3%) | 19 (18.3%) |
| >3 lesions | 34 (33.0%) | 41 (39.4%) |
| Serum Light Chain4 | | |
| Kappa | 59 (57.3%) | 53 (51.0%) |
| Lambda | 28 (27.2%) | 40 (38.5%) |
Response rate was the primary endpoint. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm (51.5% compared with 35.6% for dexamethasone alone).
Erythema Nodosum Leprosum (ENL)
The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.
Two double-blind, randomized, controlled trials reported the dermatologic response to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in weight.
Table 4: Double-Blind, Controlled Clinical Trials of Thalidomide in Patients with ENL: Cutaneous Response |
* In patients with cutaneous lesions
** Iyer: Complete response or lesions absent
** Sheskin: Complete improvement + “striking” improvement (i.e., >50% improvement)
|
| Reference | No. of
Patients | No. Treatment
Courses* | Percent Responding** |
| Iyer et al. 10 | | | Thalidomide | Aspirin |
| Bull World Health | 92 | 204 | 75% | 25% |
| Organization 1971;45:719 | | | | |
| Sheskin et al. 11 | | | Thalidomide | Placebo |
| Int J Lep 1969;37:135 | 52 | 173 | 66% | 10% |
Waters12 reported the results of two studies, both double-blind, randomized, placebo-controlled, crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.
Table 5: Double Blind, Controlled Trial of Thalidomide in Patients with ENL: Reduction in Steroid Dosage | Reference | Duration of | No. of Patients | Number Responding |
| Treatment | | Thalidomide | Placebo |
| Waters12 | 4 weeks | 9 | 4/5 | 0/4 |
| Lep Rev 1971;42:26 | 6 weeks (crossover) | 8 | 8/8 | 1/8 |
Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy.
Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population.
Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide.
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